Statistically, in the development of new medicaments, the developments for about 40% of medicaments are limited due to the water solubility problem, and some of the medicaments are even insoluble in some common organic solvents. The solubilization of water insoluble medicaments is one of important issues in pharmacy research. Common solubilization methods include modulation of pH value, use of latent solvent, cosolvent, cyclodextrin clathrate, phospholipid complex, surfactant solubilization, preparation of micelles, liposomes, microspheres, solid lipid nanoparticles, microemulsions, and fat emulsions and the like; or chemical methods of introducing water-soluble groups by utilizing suitable groups in the structure of the medicament to obtain derivates with greater water solubility.
Some medicament molecules are dissociable weak acids or weak bases. Dissociation of insoluble medicaments by adjusting the pH value of the solution is a simple and effective method for solubility improvement. In injection administration, buffer pair capacity issue should be noted. Insoluble medicaments tend to be supersaturated due to the dilution by blood, since the blood possesses good buffer ability.
For some nonpolar medicaments, the mixture of less polar organic solvents (latent solvents) with water is generally used to dissolve the medicaments. 10% of injections approved by FDA use latent solvents. This kind of formula could not only improve the solubility of some medicaments significantly, but also reduce the hydrolysis reaction of some medicaments in the solutions, thus improving the stability of the formulations. However, for some insoluble medicaments, a higher fraction of organic solvents is required for achieving the requirement of solubility. For example, phenobarbital injection requires 10% ethanol and 67.8% propylene glycol for dissolving. However, high fraction of organic solvents tends to induce local irritation of injection site and phlebitis. For example, if the formula contains more than 10% ethanol, significant pain of injection will occur.
Cyclodextrin clathration can be used to a variety of medicaments, the unique cage structure of which could form host and guest molecule complex, wherein nonpolar medicament molecules are located inside the nonpolar cage structure, and polyhydroxy outside the cyclodextrin possesses high affinity with polar water molecule, thus improving solubility. However, for some insoluble medicaments, the drug loading capacity is on the low side. The solubilization effect of medicaments in cyclodextrin depends on the binding constant of medicament molecule with cyclodextrin. For example, the binding constant of benzodiazepine medicaments is relatively low, therefore after comparison, the traditional latent solvent formula has been selected. In other words, not all medicaments could utilize cyclodextrin clathration. Furthermore, the categories of cyclodextrins are limited, and the cyclodextrins possess significant toxicity and thus not many have been used in injections currently.
In recent years, liposomes, microspheres, solid lipid nanoparticles, microemulsions, and hydrophilic derivates are used to improve the water solubility of insoluble medicaments. There are many researches and patents both at home and abroad. Although these researches have obtained some progress, there still exist problems such as the instable effect, complexity of formulation and process, low drug loading capacity, high toxicity of surfactants as well as high costs of development, and the like.
Surfactants improve the solubility of nonpolar medicaments in water by forming micelle. When used by clinical injection, many insoluble anti-tumor medicaments have to utilize surfactants for solubilization. Currently, injectable surfactants approved both at home and abroad include polysorbate (mainly POLYSORBATE 80, i.e. Tween 80), poloxamer (mainly POLOXAMER 188), Cremophor EL (mainly CREMOPHOR EL), and phospholipid. Wherein, poloxamer 188 and phospholipid have strong emulsifying ability, but are weak in solubilization, and mainly used in intravenously injectable fat emulsion. Cremophor EL and Tween 80 have relatively strong solubilization and emulsifying abilities, could solubilize insoluble medicaments into non-aqueous medium, and could form aqueous solution or emulsion by formulating with water for injection (or injectable normal saline solution, injectable dextrose solution) before use. In this kind of ready-to-use injections, the solubilization and emulsifying abilities of Cremophor EL or Tween 80 both play important roles.
For example, commercial paclitaxel, teniposide injections include a large amount of Cremophor EL, and could be formulated into an aqueous solution with aqueous medium such as water for injection before use; docetaxel injection includes a large amount of Tween 80, and could be formulated into an aqueous solution with aqueous medium such as water for injection before use; there are also many other related patent reports in which Cremophor EL or Tween 80 is selected. In Patent CN200610037337.3, phospholipid, other surfactants (Tween 80, poloxamer 188, and Cremophor EL) and non-aqueous solvents are used to prepare injections for insoluble medicament paclitaxel; Chinese Patent 200710198956.7 relates to injectable teniposide injections, which formula contains Tween 80 as surfactant. Generally, it is difficult to formulate insoluble medicament injections without Cremophor EL or Tween 80.
However, for injections, which contain Cremophor EL or Tween 80, some patients will have adverse reactions such as dermatitis medicamentosa, tachypnea, bronchospasm, hypotension, and haemolysis after administration, which results in much inconvenience for clinical use, and causes significant pain for the patients, so the compliance for medication is poor. In recent years, many researchers in the pharmacy field at home and abroad focus on the studies on new anti-tumor delivery systems for reducing or replacing Cremophor EL or Tween 80. Since these two surfactants could induce extremely severe side effects, they are limitedly used in injections. Obviously, injections without these two surfactants are more preferable for improving the compliance for medication.